Indwelling catheter with stable enzyme coating

ABSTRACT

An improved indwelling catheter adapted for long-term usage includes a stable enzyme coating to prevent occlusion of the catheter lumen. The enzyme coating includes a fibrinolytic and/or lipolytic enzyme incorporated in a catheter coating to resist or control proteolytic degradation, thereby maintaining the enzyme in an active state for dissolving clots and occlusions within the catheter lumen over an extended period of time.

This is a continuation of application Ser. No. 08/221,934, filed Apr. 1,1994.

BACKGROUND OF THE INVENTION

This invention relates generally to improvements in catheters for use indelivering medical fluids to a patient. More particularly, thisinvention relates to an improved catheter and related methods ofmanufacture, wherein the improved catheter has a stabilized enzymecoating for long-term interaction with body fluids to prevent and/ordissolve clots and occlusions within the catheter lumen.

Catheters are well-known in the medical arts for use in deliveringmedical fluids to or drawing body fluids from a patient. In one typicalform, the catheter comprises an elongated tubular element adapted fortranscutaneous placement, normally with the assistance of a withdrawablestylet needle. The catheter defines a narrow lumen or passage permittingtranscutaneous fluid transfer to or from the patient. In another typicalapplication, the catheter is implanted into the patient in associationwith an implantable infusion pump or similar instrument for programmeddelivery of a selected medication such as insulin over an extendedperiod of time. One such implantable infusion pump including animplantable catheter is shown, by way of example, in U.S. Pat. Nos.4,373,527 and 4,573,994. In either case, the catheter is commonlyconstructed from a biocompatible polymer material, such as a medicalgrade silicone rubber.

In many patient treatment applications, it is necessary or desirable forthe catheter to remain in place for an extended period of time which mayrange from several days to several years. Such long-term indwellingcatheters are routinely used, for example, for monitoring patient bloodcomponents, dialysis and hemodialysis, parenteral feeding, delivery ofcertain medications, etc. However, the catheter lumen is susceptible toocclusion which occurs as a result of complex interactions involving thecatheter material, and the simultaneous presence of infusion and bodyfluids. In some forms, catheter occlusions appear to consist primarilyof fibrin-based clots, whereas in other forms the occlusions includelipid-based substances. When an occlusion occurs, the catheter must bereplaced or the lumen otherwise cleared before infusion of the medicalfluids can be resumed. Occlusion removal in an implanted catheter can bedifficult, and removal is not a desirable alternative.

In the past, several methods have been proposed in an effort to preventcatheter occlusions or otherwise to clear the catheter lumen after ablockage has occurred. More specifically, heparin is well-known for itsanticoagulant characteristics, and is frequently used to prevent clotformation within the catheter lumen. In one approach, the catheter lumenis simply dipped in a heparin solution before patient placement, withthe dip coating being generally effective to prevent localized clottingover a relatively short period of time until the heparin is degradedupon contact with body fluids. In an alternative approach, the catheteris periodically flushed with a heparin solution in a manner leaving aquantity of residual heparin within the catheter lumen to resist clotformation when the catheter is not in use. Unfortunately, heparin isineffective to dissolve clots and/or other occlusions after formationthereof, whereby heparin usage has not provided satisfactory catheterocclusion control. Moreover, heparin has not been approved for use withsome medications, such as insulin.

Alternative occlusion control methods have utilized a fibrinolyticenzyme such as a kinase enzyme known to be effective in dissolvingfibrin-based clots. In this regard, dip coating of the catheter in asolution containing a fibrinolytic enzyme has been shown to be effectivein preventing and/or dissolving clots along the narrow catheter lumen.However, in the presence of body fluids, the fibrinolytic enzymedegrades rapidly and is thus ineffective for long-term occlusioncontrol. Any clots formed subsequent to enzyme degradation are extremelydifficult to dissolve, since it is difficult to deliver additionalenzyme solution to the blockage site along the catheter lumen.

In addition, it is believed that occlusions forming along the catheterlumen are frequently attributable at least in part and perhaps primarilyto accumulation of lipid-based substances, with fibrin-based clottinghaving a lesser role in formation of the blockage. Previous occlusioncontrol methods involving the use of heparin or fibrinolytic enzymes areineffective to break down and dissolve a lipid-based occlusion.

There exists, therefore, a significant need for further improvements inindwelling catheters and related methods for preventing and/ordissolving catheter occlusions, particularly for use in providingocclusion control over an extended period of time. The present inventionfulfills these needs and provides further related advantages.

SUMMARY OF THE INVENTION

In accordance with the invention, an improved indwelling catheter andrelated production method are provided, wherein the catheter includes astable and substantially immobilized enzyme coating to prevent formationof and/or to dissolve occlusions along the catheter lumen. The enzymecoating comprises a selected fibrinolytic and/or lipolytic enzymeapplied to the catheter, in combination with means for preventing orotherwise regulating proteolytic degradation in response to enzymeinteraction with body fluids. The thus-protected enzyme exhibitsrelatively stable characteristics, with long-term effectiveness in theprevention and/or dissolution of catheter occlusions.

In one form, the selected enzyme is applied to indwelling surfaces ofthe catheter as a thin micellar coating. A porous encapsulant such as aporous silicone rubber film is then applied to the catheter to cover andencapsulate the micellar enzyme. The porosity of the encapsulant film iscontrolled to isolate the enzyme from significant interaction withproteolytic body fluids, while permitting diffusion of other body fluidconstituents to activate the enzyme for purposes of preventing ordissolving an occlusion. For example, by controlling the porosity of theencapsulant film, a fibrinolytic enzyme can be protected againstproteolytic degradation yet interact with plasminogen to produce plasminwhich is effective in dissolving fibrin-based clots.

In an alternative form, the selected enzyme in particulate form iscoated with an encapsulant shell of starch-based material or the like,and variable coating thickness. The resultant capsules are bonded to thepolymeric surface of the catheter by silicone chemistry, such as coatingthe capsules and catheter with different silanes adapted for stablebonding upon contact therebetween. When the catheter is used, theencapsulant shells dissolve slowly to expose the enzyme in a gradualmanner over an extended period of time.

In a still further preferred embodiment of the invention, the selectedenzyme is mixed with albumin to form a slurry. The albumin is thencross-linked with the enzyme at the surface of the catheter, resultingin a cross-link chemical bond, by applying the slurry to a gel of silaneand a selected aldehyde on the catheter surface. The cross-linked enzymeis thus integrated into a membrane-like matrix on the surface of thecatheter where it is available for occlusion control but otherwiseshielded from proteolytic degradation.

Other features and advantages of the present invention will become moreapparent from the following detailed description, taken in conjunctionwith the accompanying drawings which illustrate, by way of example, theprinciples of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate the invention. In such drawings:

FIG. 1 is a perspective view illustrating a typical catheter installedtranscutaneously for infusing medication to a patient;

FIG. 2 is a enlarged fragmented sectional view illustrating the crosssectional geometry of an indwelling portion of the catheter shown inFIG. 1;

FIGS. 3-6 illustrate a sequence of process steps for applying a stableenzyme coating onto the surface of a catheter, in accordance with onepreferred form of the invention;

FIG. 7 illustrates an alternative preferred form of the invention,wherein a coating solution is sprayed onto falling enzyme particles;

FIG. 7a is an enlarged fragmented sectional view corresponding with thecoated particle identified in FIG. 7 by the encircled region 7a;

FIGS. 8-10 illustrate a sequence of further process steps, for applyingthe coated enzyme particles of FIGS. 7 and 7a to the catheter; and

FIGS. 11-13 illustrate a sequence of process steps for applying thestable enzyme coating to the surface of a catheter, in accordance with astill further alternative preferred form of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As shown in the exemplary drawings, an improved indwelling catheterreferred to generally by the reference numeral 10 is provided forlong-term infusion of medical fluids to a patient 12. The catheter 10includes a stable, substantially immobilized enzyme-containing coating14 as depicted, for example, in FIG. 6, for preventing and/or dissolvingocclusions. Proteolytic and/or chemical hydrolysis between the enzymecoating and patient body fluids, which would otherwise result in rapidenzyme degradation and deactivation, is substantially prevented orotherwise controlled in a manner rendering the enzyme available foreffective long-term occlusion control.

The catheter 10 shown in FIGS. 1 and 2 has a generally conventionalconstruction to include an elongated tubular member adapted fortranscutaneous placement on the patient 12, for use in infusing medicalfluids to or drawing body fluids from the patient. The catheter 10 istypically installed with the assistance of an elongated stylet needle(not shown) or the like which can be withdrawn from the catheter lumen16 subsequent to catheter placement. It will be understood, however,that the invention contemplates other types of catheters, particularlysuch as an implantable device adapted for use in combination with animplantable medication infusion pump or the like to deliver medicationto a patient over an extended period of time. In either form, thecatheter 10 is commonly constructed from a polymeric material, such asmedical grade silicone rubber, polyethylene, or the like.

In the course of normal catheter usage, occlusions can form along thecatheter lumen 16, particularly near the tip end thereof, as a result ofcomplex interactions involving infusion fluids, body fluids, and thepolymeric catheter material. Such occlusions are commonly associatedwith fibrin-based clots, although it is believed that lipid-basedsubstances can also play a major and even dominant role in blockageformation. The present invention relates to apparatus and method forpreventing and/or dissolving such occlusions over an extended period ofcatheter usage.

In general terms, and in accordance with the present invention, aselected enzyme effective to prevent or dissolve a catheter occlusion isapplied as an integral part of the coating 14 on the catheter 10. Afibrinolytic enzyme such as a kinase enzyme may be used for dissolvingfibrin-based clots. Examples of kinase enzymes suitable for this purposeinclude urokinase, streptokinase, and tissue plasminogen activator(TPA). Alternatively, a lipolytic enzyme such as phospholipase may beused for dissolving a lipid-based occlusion. A combination of suchfibrinolytic and lipolytic enzymes may also be used. In each case, inthe preferred form, the selected enzyme or combination of enzymes isisolated or otherwise protected against rapid proteolytic or chemicalhydrolysis breakdown in the presence of body fluid, thereby sustainingenzyme activity for long-term effectiveness in preventing catheterocclusions.

FIGS. 3-6 illustrate one preferred form of the invention, wherein theselected enzyme is mechanically trapped or retained against the surfaceof the catheter 10 by an encapsulating film 18 selected for secure filmadhesion to the polymeric catheter material. The encapsulating film 18is produced with a controlled porosity to protect and isolate the enzymefrom proteolytic components in body fluid, while permitting enzymeactivity to reduce or eliminate catheter blockages.

More specifically, FIG. 3 illustrates immersion of catheter 10 into aprepared enzyme slurry or emulsion 20. In this regard, the enzyme iscommonly available in particulate form, having a particle size rangingon the order of one to fifteen microns. The enzyme particles are mixedin a liquid carrier such as water to produce the emulsion 20 shown inFIG. 3. Upon withdrawal of the catheter 10 from the enzyme emulsion 20,the catheter surface is allowed to dry resulting in adherence of theenzyme to the catheter in a micellar array of microsphere particles 21,as shown in exaggerated form in FIG. 4.

The encapsulating film 18 is prepared as shown in FIG. 5, in the form ofdilute silicone rubber. In particular, in accordance with one preferredform of the invention, a silicone rubber elastomer and curing agent suchas those marketed by Dow Corning Corporation of Midland, Mich., underthe designation Silastic MDX4-4210, is mixed in a ratio of about 35 to 1by volume, and then diluted by addition of water. The resultant solution22, when applied to the catheter and cured in film form, adheressecurely to the polymeric catheter material while providing a controlledporosity in accordance with the proportion of water addition. Apreferred water proportion is on the order of 30 to 35 percent, toprovide a resultant film pore size of about 1,000 Å.

The catheter 10 prepared in accordance with FIGS. 3 and 4, is dippedinto the uncured film solution 22 of FIG. 5, and then withdrawn topermit curing of the encapsulant film 18 thereon. As shown inexaggerated form in FIG. 6, the silastic-based film adheres to thecatheter in the spaces between the enzyme micells 21, while providingthe protective film 18 which encapsulates and isolates the enzymeparticles from adjacent body fluids. The controlled porosity of the film18 permits diffusion passage of body fluid constituents to activate theenzyme, such as plasminogen which results in production of plasmin forsolubilizing fibrin-based clots. Larger and more complex molecules suchas proteolytic-based substances within the body fluid are isolated bythe film 18 from the enzyme, thereby shielding the enzyme fromsignificant proteolytic body fluid breakdown.

FIGS. 7-10 illustrate an alternative preferred form of the invention,wherein the enzyme particles 24 are integrated into time releasecapsules 26 which are mounted in turn by chemical bonding onto thecatheter surface. The capsules 26 include variable coating thicknessesfor dissolution at different times in the presence of body fluids,thereby exposing the encapsulated enzyme particles 24 over an extendedtime period for occlusion control.

FIG. 7 illustrates capsule formation by spraying a stream 28 of acoating solution through an intersecting stream of falling enzymeparticles 24. A preferred encapsulant coating solution comprises astarch-based substance such as a selected polysaccharide mixed within anon-protein or aprotic solvent such as acetonytrile. Alternatively,enzyme particles 24 may be blown through an encapsulant bath. In eithercase, the resultant enzyme-containing capsules 26 are produced with ashell 25 having a variable thickness ranging on the order of about 0.02to 7 microns.

The capsules 26 are then bonded to the polymeric catheter material bysilicone chemistry. More specifically, the catheter 10 and the capsules26 are surface-coated with silane compounds adapted for secure bondingfirst to the polymeric catheter material and then in turn to thecapsules 26. As an example, the catheter 10 is dip coated (FIG. 8) witha first silane compound 30 such as mercaptosilane having a secondfunctional group for covalent bonding with the catheter material. Thecapsules 26 are coated as by spraying with a second and different silanecompound (not shown), such as a long alkylamino silane. The thus-coatedcapsules are then chemically bonded to the silane-coated catheter byimmersing the catheter in a dilute hydrochloric acid solution 31 andwith the capsules 26 added thereto (FIG. 9).

FIG. 10 illustrates in enlarged and exaggerated form, an array of thetime release capsules 26 securely bonded to the exterior of the catheter10. In use, the encapsulant material on the capsules 26 is of varyingthickness and dissolves in the presence of body fluid, resulting intime-release exposure of the enzyme particles 24 over an extended timeperiod, for corresponding occlusion control over an extended timeperiod.

FIGS. 11-13 depict a further alternative preferred form of theinvention, wherein the enzyme is securely attached by cross-link bondingto the polymeric catheter material. The cross-link bond is in a matrixwith a serum protein such as albumin, which has been found to shield orisolate the enzyme from proteolytic breakdown in the presence of bodyfluids.

FIG. 11 illustrates dip immersion of the catheter 10 into a solution 32prepared from a selected silane 33 and a selected aldehyde 34 such asglutaraldehyde or formaldehyde. This initial surface coating on thecatheter is securely and covalently bonded to the polymeric cathetermaterial by means of the silane group in the same manner as previouslydescribed with respect to FIG. 8. However, in this embodiment, thesilane also bonds chemically with the aidehyde. The thus-coated catheteris then dip immersed into a gel solution 35 formed from the selectedenzyme 36 and a serum protein such as albumin 38, in a saline solution(FIG. 12) at a concentration of about five percent albumin. Across-linked membrane 40 (FIG. 13) is thus produced on the surface ofthe catheter 10, wherein the membrane cross-links the enzyme with thealbumin, by means of the aidehyde, to provide a proteolytic resistantstructure. However, the enzyme is available for solubilizing catheterocclusions.

With a fibrinolytic enzyme, the enzyme combines with plasminogenavailable in patient body fluid to produce plasmin. The plasmincooperates in turn with fibrin present in a fibrin-based clot to producesoluble fibrinogen and other constituents. In effect, the enzyme thuscombines with available plasminogen to dissolve a fibrin-based clot. Bycontrast, with a lipolytic enzyme, the enzyme combines with grease orsoap-like phospholipids produced in the presence of body fluids andcertain medications, to produce soluble lipase compounds. For example,zinc compounds are commonly used to stabilize certain medications suchas insulin, wherein such zinc compounds are believed to combine withphospholipids in body fluid to generate a soap-like lipid-basedsubstance which can accumulate within and occlude the catheter lumen. Inthe presence of the lipolytic enzyme, the occlusion is dissolved. In thepresent invention, the selected enzyme applied to the catheter maycomprise a fibronolytic or lipolytic enzyme, or a combination thereof.

A variety of further modifications and improvements to the presentinvention will be apparent to those skilled in the art. AccordinglY, nolimitation on the invention is intended by way of the foregoingdescription and accompanying drawings, except as set forth in theappended claims.

What is claimed is:
 1. A catheter, comprising:an elongated tubularelement formed from a polymeric material and adapted for patientplacement, said tubular element defining a catheter lumen; and a surfacecoating applied to said tubular element on at least a portion of thesurface thereof, said surface coating including at least one enzymeeffective to dissolve occlusions along said catheter lumen, and meansfor protecting said enzyme against short-term degradation upon contactwith patient body fluids; said at least one enzyme comprising asubstantially micellar array of enzyme particles on said tubularelement, and further wherein said enzyme protecting means comprises aporous encapsulant film covering said enzyme particles and adheringsecurely to said tubular element, said encapsulant film having acontrolled porosity to permit diffusion passage of body fluidconstituents effective to activate the enzyme for occlusion controlwhile substantially shielding the enzyme against degradation; said atleast one enzyme being selected from the group consisting of urokinase,streptokinase, tissue plasminogen activator (TPA) and phospholipase, andmixtures thereof.
 2. The catheter of claim 1 wherein said encapsulantfilm comprises dilute silicone rubber.
 3. A method of applying an enzymecoating to a polymeric catheter, said method comprising the stepsof:applying a selected enzyme to at least a portion of the surface ofthe catheter in a substantially micellar array, said at least one enzymebeing selected from the group consisting of urokinase, streptokinase,tissue plasminogen activator (TPA) and phospholipase, and mixturesthereof; and encapsulating the micellar array of enzyme with a porousencapsulant film covering the enzyme and adhering to the catheter toretain the enzyme against the catheter surface, for activation upondiffusion passage of patient body fluid constituents to dissolvecatheter occlusions.
 4. The method of claim 3 wherein said step ofapplying the enzyme in micellar array to the catheter comprises mixingenzyme particles with water to form an enzyme slurry, dipping thecatheter into the enzyme slurry to coat a portion of the cathetersurface with the enzyme slurry, and allowing the enzyme slurry to dry onthe catheter.
 5. The method of claim 3 wherein said step ofencapsulating the micellar array of enzyme comprises preparing a filmsolution containing silicone rubber elastomer and curing agent, dippingthe catheter with micellar enzyme array thereon into the film solutionto form the encapsulant film, and allowing the encapsulant film to curein place on the catheter.
 6. The method of claim 5 wherein said filmsolution preparing step comprises mixing the film solution withsubstantial excess elastomer.
 7. The method of claim 6 wherein said filmsolution preparing step further includes diluting the film solution withwater.